CN1303271A - Preparations for application of anti-inflammatory, especially antiseptic agents and/or agents promoting healing of wounds, to lower respiratory tract - Google Patents

Preparations for application of anti-inflammatory, especially antiseptic agents and/or agents promoting healing of wounds, to lower respiratory tract Download PDF

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CN1303271A
CN1303271A CN99806577A CN99806577A CN1303271A CN 1303271 A CN1303271 A CN 1303271A CN 99806577 A CN99806577 A CN 99806577A CN 99806577 A CN99806577 A CN 99806577A CN 1303271 A CN1303271 A CN 1303271A
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method
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liposomes
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沃尔夫冈·弗莱舍
卡伦·赖默
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尤罗塞尔蒂克股份有限公司
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/10Dispersions; Emulsions
    • A61K9/127Liposomes
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02ATECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection
    • Y02A50/30Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
    • Y02A50/46Medical treatment of waterborne diseases characterized by the agent
    • Y02A50/462The waterborne disease being caused by a virus
    • Y02A50/465The waterborne disease being caused by a virus the virus being the poliovirus, i.e. Poliomyelitis or Polio

Abstract

消炎剂诸如聚乙烯吡咯酮碘用于制备治疗对给予这类活性剂敏感的下呼吸道疾病的药物组合物的用途。 Anti-inflammatory agents such as betadine for the preparation of the treatment of sensitive administering such agents in the pharmaceutical compositions of respiratory diseases.

Description

施用于下呼吸道的消炎剂,特别是抗菌剂和/或促进伤口愈合活性剂的制剂 Anti-inflammatory agent is administered to the lower respiratory tract, especially antibacterial agents, and / or promoting wound healing of the active agent formulation

本发明涉及施用于下呼吸道的具有抗炎作用,特别是具有抗菌/或促进伤口愈合特性的活性剂的制剂。 The present invention relates to the formulation to the respiratory tract have anti-inflammatory effects, in particular with antimicrobial agents / or promoting wound healing properties of. 将所述的制剂特别施用于人和动物下呼吸道中的气管、支气管和肺泡。 The particular formulation to the respiratory tract in humans and animals of the trachea, bronchi and alveoli.

此外,本发明涉及通过施用一种药物制剂来预防和治疗感染的方法。 Further, the present invention relates to methods for the prevention and treatment of infections by administering a pharmaceutical formulation.

公知大量不同的抗菌素和抗菌剂用于局部治疗感染性疾病。 Large number of different known antibiotics and antimicrobial agents for topical treatment of infectious diseases. 抗菌素活性剂的明显缺陷在于感染细菌对这些药物表现出初步的耐受性且可以获得中度的耐受性。 Obvious defects antibiotic agents is that the infecting bacteria to these drugs exhibit initial resistance and the resistance can be achieved moderate. 此外,抗菌素通常会导致患者的致敏作用。 In addition, antibiotics usually leads to sensitization of the patient. 例如释放卤素的抗菌剂诸如聚乙烯吡咯酮碘,也称作PVP-碘,即聚(1-乙烯基-2-吡咯烷-2-酮)-碘配合物可以预防耐受性。 E.g. halogen-releasing antibacterial agents such as povidone iodine, also known as PVP- iodine, i.e. the poly (1-vinyl-2-pyrrolidin-2-one) - iodine complex resistance can be prevented. 与抗菌素相比,抗菌剂很少过敏。 Compared with antibiotics, antibacterial agents rarely allergies.

目前,用抗菌素治疗呼吸道的感染性疾病。 At present, with antibiotic treatment of infectious diseases of the respiratory tract. 经呼吸道施用抗菌素活性剂已经成为几种着重于下呼吸道的综述和论文的研究主题。 Administration of antibiotic agents via the respiratory tract has been focused on a review of several papers and lower respiratory tract of research topics. 例如,Ramsey等在“新英格兰药物杂志”(“The New England Journal of Medicine”)1999年第340卷第1期第23-30页中描述了对患囊性纤维化病人周期性给予可吸入妥布霉素。 For example, Ramsey et al, "New England Journal of Drug" on page 23-30 ( "The New England Journal of Medicine"), 1999, Vol. 340 No. 1 described in administering to patients suffering from cystic fibrosis periodically inhalable duly ADM cloth.

Wiener-Kronish在“抗菌化疗杂志”(“Journal of Antimicrobio1Chemotherapy”)(1996)38,第809-818页中研究了雾化亚胺培南/西司他丁用于预防假单胞菌属诱发的急性肺损伤。 Wiener-Kronish studied the atomization of imipenem 38, pp. 809-818, "Antimicrobial Chemotherapy" ( "Journal of Antimicrobio1Chemotherapy") (1996) in / cilastatin for the prevention of Pseudomonas-induced acute lung injury.

Schreier在几种近期的综述例如在“脂质体的药物应用”(“Medicalapplications of liposomes”),Papahadjopoulos和Lasic(编辑),Elsevier 1998)中描述了给肺部施用不同的抗菌素活性剂象青霉素G、妥布霉素或阿卡米星用于治疗感染性疾病。 Schreier in several recent review, for example, in the "pharmaceutical applications of liposomes" ( "Medicalapplications of liposomes"), Papahadjopoulos and Lasic (editor), Elsevier 1998) describes the antibiotic to the pulmonary administration of the different active agents like penicillin G , tobramycin or Kami star for the treatment of infectious diseases.

然而,用抗菌素治疗可导致本领域技术人员所公知的并发症。 However, treatment with antibiotics can lead to the skilled person known complications. 例如,通常用抗菌素治疗患急性或慢性支气管炎的病人以便缓解症状。 For example, typically the treatment of patients suffering from acute or chronic bronchitis with antibiotics in order to alleviate the symptoms. 这通常仅能产生导致症状细菌的耐受性。 This usually results in tolerance symptoms only produce bacteria. 许多呼吸道疾病是由病毒引起的。 Many respiratory diseases are caused by a virus. 抗菌素对这类情况无效且不能治愈这类病人的感染。 Antibiotics in such cases is invalid and can not cure the infection in such patients.

对人和动物外用抗菌剂和/或促进伤口愈合活性剂公开在我们的早期专利EP 0 639 373中。 Topical antimicrobial agents on humans and animals and / or promoting wound healing agents disclosed in our earlier patent EP 0 639 373 in. 特别地,在该文献中证明PVP-碘的脂质体制剂可局部施用于眼外部。 In particular, in this document demonstrate PVP- iodine liposome formulations may be topically applied to the eye outside. 这些制剂一般采用乳膏剂、软膏剂、洗剂、凝胶体或滴剂的剂型。 These formulations generally use creams, ointments, lotions, gel or drop dosage forms.

脂质体是众所周知的药物载体且由此脂质体剂型的药剂的应用在相当长时间内已经成为研究的主题。 Liposomes are well-known drug carriers and therefore the application of liposomal formulations of the drug in quite a long time been the subject of research. 综述“脂质体的肺部转运”(“Pulmonarydelivery of liposomes”)(H.Schreier在“控释杂志”(“Journal of ControlledRelease”)24,1993,209-223页)中提供了涉及哮喘疗法中使用肺部转运脂质体包囊的药物的综述。 Summary of "lung transporter liposomes" ( "Pulmonarydelivery of liposomes") (H.Schreier in the "Journal of Controlled Release" ( "Journal of ControlledRelease") 24,1993,209-223 page) provides involving in asthma therapy use the lungs transporters of liposome encapsulated drug review. 在该文献中证明了脂质体气雾剂的物化特征及其对呼吸道的治疗应用。 The physicochemical characteristics of the liposomes proved aerosol and therapeutic applications to the respiratory tract in this document. 已经研究的通过脂质体进行肺部转运的药物包括例如抗癌药、肽类、酶类、止喘药和抗过敏化合物以及如上所述的抗菌素。 Pulmonary transport have been studied by liposomes include e.g. anti-cancer drug drugs, peptides, enzymes, antiasthmatic and antiallergic compounds as well as antibiotics as described above. H.Schreier还在“脂质体粉状气雾剂的制剂和体外特性”(“Formulation and in vitroperformance of liposome powder aerosols”)(STP《药物科学》(Pharma.Sciences)4,1994,38-44页)中描述了脂质体气雾剂或使用例如干粉吸入器的脂质体粉末气雾剂的制剂。 H.Schreier also "Formulation and in vitro properties of the liposome powder aerosols" ( "Formulation and in vitroperformance of liposome powder aerosols") (STP "Pharmaceutical Sciences," (Pharma.Sciences) 4,1994,38-44 p) describes the use of liposome aerosols or liposome formulations, for example, a dry powder inhaler powder aerosols.

正如可以从引述的文献中所观察到的,尽管已经将许多注意力集中到脂质体作为药物载体上,但是看起来现有技术中还没有涉及将脂质体和其它颗粒作为施用于体内特别是包括气管、支气管和肺泡在内的下呼吸道内的消炎剂,特别是抗菌剂和/或促进伤口愈合的活性剂的载体。 As it can be observed from the literature cited, though much attention has been concentrated on the liposomes as drug carriers, but it looks like the prior art are not directed to liposomes and other particulates as particularly applied to in vivo anti-inflammatory agent in the lower respiratory tract including the trachea, bronchi and alveoli, including, in particular antibacterial and / or wound healing promoting agent carrier.

上述现有技术中的某些涉及脂质体制剂。 Some relates to liposomal formulations of the above-described prior art. 应理解具有类似颗粒特性的可选择的药物载体是存在的。 Pharmaceutical carrier particles have similar properties to be understood that alternative exists. 这些药物载体可以经常使用且也在本发明的说明书中使用以替代脂质体,所述药物载体包括微球体(一般包括亲脂性聚合物)、纳米颗粒、“大孔颗粒”和例如通过使用脉冲激光沉积(PLD)技术制成的各自包裹的药物物质分子。 These instructions are often used pharmaceutical carriers and can also be used in the present invention, the liposomes Alternatively, the pharmaceutical carrier include microspheres (generally comprising lipophilic polymers), nanoparticles, "macroporous particles" and such as by using a pulse drug substance made of molecules each wrapped laser deposition (PLD) techniques. 可以将这些PLD法用于将包裹材料施用于药粉上并改变各种药物系统的表面特性和释放速率。 These PLD methods can be used for the powder coating material is applied to the modified surface properties and the various systems and the release rate of drug.

在下文涉及的内容是针对脂质体或颗粒载体的,但是应理解也可以混合这类可选择的载体。 The following relates to the content is directed to liposomes or particulate carriers, it is to be understood that such alternative carriers may be mixed.

本领域中公知通过雾化或喷雾脂质体、微球体、大孔颗粒、PLD或纳米颗粒制剂或通过吸入相应制剂的干粉可以实现可吸入颗粒向呼吸道给药。 Is well known in the art by atomization or spray, liposomes, microspheres, macroporous particles, the PLD or nanoparticle preparations or may be implemented inhalable particles to the respiratory tract by inhalation of a dry powder corresponding formulation.

除可能在威胁到生命的败血病并发症的紧急情况外,看起来给身体内部施用消毒剂在本领域中存在明显的障碍。 In addition to the possible threat to the life of septic complications in emergency situations, to look inside the body administering the disinfectant obvious obstacles in the art.

一般来说,即使有上述缺陷,抗菌素制剂看起来也是优选的。 In general, even if the above drawbacks, antibiotic preparations appear also preferred.

本发明的一个目的是提供一种具有良好接受性的易施用的消炎,特别是抗菌和/或促进伤口愈合的制剂,该制剂可使活性剂在下呼吸道内产生延长的释放和延长的局部作用。 An object of the present invention is to provide acceptable anti-inflammatory properties having good ease of application, in particular an antibacterial and / or wound healing promoting preparation, the formulation of active agents can produce localized release and prolonged action of the lower respiratory tract prolonged.

根据本发明,这一目的可以达到,即所述的制剂在颗粒载体制剂形式中含有至少一种消炎剂,特别是抗菌剂和/或促进伤口愈合的活性剂,正如独立权利要求1中所限定的。 According to the invention, this object is achieved in that the formulation comprises at least one anti-inflammatory agent in the form of a particulate carrier preparation, especially antibacterial agents, and / or promoting wound healing agents, as defined in an independent claim of.

本发明进一步包括一种治疗人和动物下呼吸道的方法,正如独立权利要求21和22中所限定的。 The present invention further includes a method of treating lower respiratory tract in humans and animals, as claimed in the independent claims 21 and 22 is defined.

从属权利要求限定了本发明另外优选的实施方案。 It defines a further preferred embodiment of the present invention, the dependent claims.

在本发明的说明书中,将消炎剂理解为包括如下所述的抗菌剂、抗菌素活性剂、皮质甾类和愈合伤口的活性剂。 In the present specification, the antiinflammatory agent will be understood to include the following antimicrobial agents, antibiotic agents, corticosteroids and healing agents.

在本发明的说明书中,将抗菌剂理解为包括药物上可接受的和适于在一定程度上治疗下呼吸道的可按照本发明配制它们的那些消毒剂。 In the present specification, the antibacterial agent will be understood to include pharmaceutically acceptable may be formulated and adapted for respiratory therapy according to the present invention under a certain degree that their disinfectant.

更具体地说,抗菌剂特别包括释放氧的化合物和释放卤素的化合物;金属化合物诸如银和汞化合物;有机消毒剂特别包括释放甲醛的化合物、醇类、苯酚类包括烷基和芳基苯酚类以及卤代苯酚类、喹啉类和吖啶类、六氢嘧啶类、季铵化合物和亚胺鎓盐、和胍类。 More specifically, the antibacterial compounds to release oxygen and halogen-releasing compounds include, in particular; metal compounds such as silver and mercury compounds; in particular, organic disinfectants including formaldehyde-releasing compounds, alcohols, phenols including alkyl and aryl phenolic benzene and halogenated phenols, quinolines and acridines, hexahydropyrimidine, quaternary ammonium compounds and iminium salts, and guanidines.

促进伤口愈合的活性剂包括促进肉芽发生和上皮形成的活性剂诸如泛醇、尿囊素类、甘菊环烃类、单宁类和维生素B类化合物。 Promoting wound healing agents include agents promoting granulation and epithelialization occurs such as panthenol, allantoin type, azulene-based, tannins and vitamin B compounds.

本发明根据令人意外的事实,即颗粒载体特别是脂质体,也包括微球体、纳米颗粒和包裹的药物物质分子非常适合用作施用于下呼吸道的抗菌剂特别是聚乙烯吡咯酮碘的载体和促进伤口愈合的活性剂的载体。 According to the present invention is surprising fact that particulate carriers especially liposomes, but also microspheres, nanoparticles and the entrapped drug molecules of the substance is suitable for use as an antibacterial agent administered to the lower respiratory tract, especially povidone iodine the carrier and the carrier to promote wound healing active agents.

本发明的制剂使得延长释放所述的一种或多种活性剂成为可能,并通过与细胞表面的相互作用而在所需位置上产生了延长的和局部活性。 Formulations of the invention enables prolonged release of one or more active agents according to possible, and generating an extended and topical activity at the desired position by interaction with the cell surface.

另一方面,本发明以进一步令人意外和出人意料的事实为基础。 On the other hand, the invention further surprising and unexpected fact based. 在本领域中众所周知新的身体组织的形成可以产生难题。 The formation of new body tissues are well known in the art can produce problems. 因此,身体组织的修复可以伴有疤痕组织的形成,这在功能上和/或整容上可以是有害的或者至少是不需要的。 Thus, repair of body tissues may be associated with the formation of scar tissue, which can be harmful or functionally and / or at least plastic surgery is not required. 角化过度症和不加控制的组织增殖可以引起严重的损害,从而导致功能障碍且当然也是整容上所不需要的。 Hyperkeratosis and uncontrolled proliferation of tissue may cause serious harm, leading to dysfunction and of course, you do not need plastic surgery on. 在感染和炎症发生后,组织的重新生长和愈合可以产生赘生物和共生物。 After infection and inflammation, tissue regrowth and healing and can be co-produced biological neoplasm. 因此,本领域中众所周知在治疗疾病的过程中,适当改型组织不仅是需要的,而且实际上也是必须的。 Therefore, known in the art in the treatment of disease, the appropriate modifications organizations not only need, but actually necessary.

目前令人意外地发现将抗炎活性剂单独使用或与其它这类活性剂共同使用在组织修复和其它组织生长过程中几乎不会明显导致形成不需要的身体组织。 It has now surprisingly found that the use of anti-inflammatory activity alone or in tissue repair and other tissue growth processes in combination with other active agents such little obvious cause formation of undesirable body tissue. 因此,不仅在皮肤中而且在粘膜和其它组织诸如肌肉或内部器官组织中形成的疤痕组织减少。 Thus, not only but also reduce the formation of scar tissue in the mucosa and other tissues such as muscle or an internal organ tissue in the skin. 角化过度症可以被完全抑制且在治疗感染性疾病的过程中共生物或赘生物的形成也明显减少。 Hyperkeratosis can be completely suppressed and the formation of biological or neoplastic processes of CPC treatment of infectious diseases is also reduced significantly.

本发明达到的一个目的由此与改善身体组织的修复相关。 An object of the present invention achieves thus associated with improved repair body tissue. 本发明通过以如独立权利要求中所限定的颗粒载体制剂形式施用抗炎活性剂而实现了这一目的。 The present invention this object is achieved by administering an anti-inflammatory agent in the form of a particulate carrier preparation as defined in the independent claims of.

通过雾化装载有活性剂的颗粒载体制剂,或通过吸入相应制剂的干粉可以对呼吸道给药消炎、抗菌和/或愈合伤口的制剂。 By atomization particulate carrier loaded with an active agent formulation, or by dry powder inhalation of the respective formulations to the respiratory tract can be anti-inflammatory, antibacterial and / or wound healing preparations. 例如,通过用常用方法使脂质体载有PVP碘可以制备脂质体制剂。 For example, liposome formulations may be prepared by conventional methods using liposomes containing PVP iodine.

还能够将加载的脂质体任何与辅助物质诸如低分子糖类,优选乳糖,一起压成致密压紧的固体药剂储备物。 Is also possible to load liposomes with any auxiliary substances such as low molecular sugars, preferably lactose, pressed together into a dense compacted solid medicament stock material. 然后可以将这种药剂储备物研磨或微粉化或以其它方式处理得到颗粒型粉。 Such medicament stock can then be triturated or micronized or otherwise treated to obtain powder particle type. 例如,如“脂质体气雾剂吸入法对健康人志愿者肺功能的急性作用”(Thomas等《初步报告》(Preliminary report)1991年第99卷第1268-1270页)中所述,可以将所得的脂质体制剂通过吸入粉末气雾剂形式的该制剂的方式来给药。 For example, as "acute effect of liposomal aerosol inhalation lung function of healthy human volunteers" (Thomas and other "preliminary report" (Preliminary report) on page 1991, 1268-1270 99 volumes) in the can the resulting liposomal formulation is administered by way of inhalation of the powder aerosol formulation. 用于制备所述致密压紧的固体药剂储备物的压力优选在50-500MPa的范围。 Pressure for preparing the densified compacted solid medicament stock material is preferably in the range of 50-500MPa. 这类药剂储备物描述在WO94/14490中、而给药装置公开在WO 93/24165中。 Such agents were described in reserve WO94 / 14490, the drug delivery device is disclosed in WO 93/24165 in.

脂质体的性质或构造一般并不关键。 Nature or structure of the liposomes is generally not critical. 例如,通过吸入气雾剂可以给药如EP 0 639 373中所述的脂质体制剂。 For example, liposome formulations may be administered as described in EP 0 639 373 an aerosol by inhalation. 将EP 0 639 373的公开内容引入本说明书作为参考。 The disclosure of EP 0639373 is incorporated herein by reference.

本发明的制剂显然不仅含有包裹在颗粒载体,特别是脂质体中的活性剂,象聚乙烯吡咯酮碘。 Formulations of the invention is clearly not contain encapsulated in the particulate carrier, especially in liposomes the active agent, like povidone iodine. 看起来还有一定量的没有包含在载体内部的药物。 There seems no amount of drug contained in the interior of the carrier. 本发明的制剂通常表现出明显的初始作用,这种作用是除活性剂从载体中缓慢、延长释放以外另外观察到的。 Formulations of the invention generally exhibit significant initial effect, which is further observed in addition to the active agent from the carrier slowly, than extended release. 这种作用特别在载体包括脂质体的情况中观察到。 This effect is especially observed where the carrier comprises a liposome. 尽管不希望结合任何理论上的解释,但是目前设想除包裹在脂质体内的活性剂外,某些活性剂还存在于脂质体外部且可能松散地结合在脂质体的外表面。 While not wishing to bound to any theoretical explanation, it is currently contemplated that other liposome encapsulated in an outer agent, some active agent also present in the liposome may be external and loosely bound on the outer surface of the liposome. 这可能是因为活性剂分子与脂质体膜结合所导致的或可能是因为在脂质体表面上形成一层的活性剂分子导致的,所述的层部分或乃至完全在外表上包裹脂质体。 This is probably because the active agent molecules bound to the liposome membrane or may be caused due to the formation of the liposome surface layer due to active agent molecules, said layer partially or even completely wrapped in the outer lipid body. 这种初始活性剂作用的类型和量可以例如受到所选择的浓度参数的影响。 The type and amount of this initial agent effect can be affected by, for example, the concentration of the selected parameters.

在本发明的说明书中可以使用现有技术中一般公知可形成脂质体膜的两亲物质,条件是对于所需的应用来说它们是药物上可接受的。 In the present specification may be used in the prior art generally known in the amphipathic substance may be formed liposome membrane, the conditions required for the applications that are pharmaceutically acceptable. 目前,含有卵磷脂的脂质体成形系统是优选的。 Currently, liposome forming systems comprising lecithin are preferred. 这类系统除含有胆甾醇和琥珀酸二钠-六水合物外还可以含有氢化大豆卵磷脂;目前特别优选的是使用氢化大豆卵磷脂作为唯一的成膜剂。 Such systems in addition to containing cholesterol and disodium succinate - outer hexahydrate may also contain hydrogenated soybean lecithin; currently particularly preferred to use hydrogenated soy lecithin as the sole film-forming agent.

上述文献中描述了形成脂质体结构的现有技术中的公知方法且一般可以将它们用于本发明的说明书中。 Described in the literature the above well-known prior art method for forming the liposome structure and generally they can be used in the description of the present invention. 概括地说,这些方法包括机械搅拌含有成膜物质和水或水溶液的合适混合物。 Broadly, these methods comprise mechanical agitation a mixture comprising a suitable film-forming substance and water or an aqueous solution. 在形成基本上均匀大小的脂质体的过程中优选通过合适的膜过滤。 In the process of forming a substantially uniform liposome size preferably by a suitable membrane.

本发明脂质体的平均大小可以在较宽的范围内改变,一般直径约为1-约50μm、优选的直径范围约1-约30μm。 The average size of the liposomes of the present invention can be varied over a wide range, typically from about 1 to about 50 m in diameter, preferably a diameter ranging from about 1 to about 30μm. 对于溶液来说,较小的平均直径、例如直径约为100nm可能更为合适。 For solutions, the smaller average diameter, for example, a diameter of about 100nm may be more appropriate.

本发明脂质体具有的基本上均匀的大小范围是:施用于气管的直径范围约20μm-30μm;施用于支气管的直径范围是约10μm-20μm;且施用于肺泡的直径范围是约1μm-6μm、特别是在2-5μm。 Liposomes of the invention have a substantially uniform size ranges are: pipe diameter in the range from about administered to a 20μm-30μm; administered to bronchial diameter ranging from about 10μm-20μm; diameter range and applied to the alveoli is approximately 1μm-6μm , especially in the 2-5μm.

如果使用另一种颗粒载体,那么它们一般如本领域中公知的方法制备。 If another carrier particles, so they are generally prepared as known in the art methods. 因此,如例如WO 95/15118中所述来制备用于转运极宽范围治疗剂或美容剂的微球体。 Thus, as for example in WO 95/15118 to prepare microspheres for the transport of a very wide range of therapeutic or cosmetic agents.

在某些情况中可以使用纳米颗粒,条件是它们可以载有足量的活性剂且可以按照本发明对下呼吸道给药。 In some cases, the nanoparticles may be used, provided that they can contain a sufficient amount of active agent and may be administered to the lower respiratory tract according to the present invention. 按照本领域中公知的方法、如例如Heyder(GSF Munchen)在“转运到肺部的药物”(“Drugs delivered to thelung”-,Abstracts IV,Hilton Head Island Conference,1998年5月)中所述可以制备它们。 According to the methods known in the art, such as e.g. Heyder (GSF Munchen) in the "transport drugs to the lungs" ( "Drugs delivered to thelung" -, Abstracts IV, Hilton Head Island Conference, May 1998) may be in the to prepare them.

在短的非水法中使用脉冲激光沉积(PLD)仪和聚合靶物将包裹层施用于药粉的方法也适于形成本发明的颗粒制剂。 The target instrument and polymeric layer is applied to a method for wrapping a particle powder formulations of the invention are also suitable for formation using a pulsed laser deposition (PLD) in a short non-aqueous process. 例如,Talton等已经在“用于改善干法转运的新型包裹法”(“Novel Coating Method for Improved DryDelivery”,Univ.of Florida UF 1887(1998))中描述了这些方法。 For example, Talton et been in the "new wrapping method for improving the dry transport" ( "Novel Coating Method for Improved DryDelivery", Univ.of Florida UF 1887 (1998)) These methods are described.

另外合适的转运系统使用了如David A.Edwards等在“用于肺部药物转运的大孔颗粒”(《科学》(Science)1997年6月20日第276卷第1868-1871页)中所公开的大孔颗粒。 Also suitable transport systems and other uses such as David A.Edwards in "macroporous particles for pulmonary drug transport" ( "Science" (Science) volume 276, page 1868-1871, 1997 June 20) in the open macroporous particles. 例如,施用于肺泡的本发明大孔颗粒直径可以在约5-20μm的范围。 For example, the scope of the present invention, the particle diameter of the macropores is applied to the alveoli of about 5-20μm.

优选的抗炎活性剂包括抗菌剂、抗菌素、皮质甾类和促进伤口愈合的活性剂,可以将它们作为单一物质使用或彼此结合使用。 Preferred anti-inflammatory agents include antibacterial agents, antibiotics, corticosteroids and agents promoting wound healing, they may be used as a single substance or in combination with each other.

优选的抗菌剂包括众所周知的可产生快速作用、具有广谱活性、低全身毒性和良好的组织相容性的药物物质。 Preferred antimicrobial agents include the well-known quick action can be generated, the drug substance having compatibility spectrum of activity, low systemic toxicity and good tissue. 例如,它们可以选自下列物质组:金属化合物、酚类化合物、洗涤剂、碘和碘配合物。 For example, they may be selected from the following group of substances: metal compounds, phenolic compounds, detergents, iodine and iodine complexes. 特别优选的抗菌剂是聚乙烯吡咯酮碘。 Particularly preferred antibacterial agent is povidone iodine.

优选促进伤口愈合的活性剂包括已经在本申请文献中描述的物质。 Preferably promoting wound healing agents include materials have been described in the present application document. 优选的这类活性剂包括公知用于促进上皮形成的物质。 Preferred such agents include substances known to promote epithelialization. 这些物质包括维生素、特别是来自维生素B族的维生素;尿囊素;某些苷葡环烃类等。 These include vitamins, particularly from the vitamin B vitamins; allantoin; some glucoside glucoside cyclic hydrocarbons.

某些目前本发明非常优选的实施方案包括在组织修复,特别是关于功能和整容组织改型中表现出有利作用的抗炎活性剂或这类活性剂的组合物。 Very certain presently preferred embodiments of the invention include tissue repair, especially with regard to functional and cosmetic tissue modification composition exhibit a beneficial effect or anti-inflammatory activity of such agents. 在这些实施方案中,活性剂通常是抗菌剂诸如PVP-碘或抗菌素。 In these embodiments, the active agents are typically antimicrobial agents such as antibiotics or PVP- iodine.

在优选的实施方案中,含有消炎剂,特别是抗菌剂和/或促进伤口愈合活性剂的本发明制剂可以进一步含有诸如麻醉剂这样的活性剂。 In a preferred embodiment, the anti-inflammatory agent containing, in particular antibacterial and / or promoting wound healing agent of the formulations of the invention may further contain such active agents such as anesthetic agents. 本发明制剂还可以含有另外常用的试剂包括佐剂和添加剂、抗氧化剂、保存剂或形成稠度的试剂诸如粘度调节添加剂、乳化剂等。 Formulations of the invention may further contain additional agents include conventional adjuvants and additives, antioxidants, preserving agents or consistency forming agents such as viscosity adjusting additives, emulsifiers and the like.

一般来说,根据这类可选择的载体来选择制剂的浓度、颗粒大小、活性剂的承载量等以便基本上符合本文所述关于脂质体制剂的参数。 Generally, the concentration of selected particle size, carrying capacity, etc. The active agent formulation such alternative carriers to substantially conform to the parameters on the liposomal formulations described herein. 选择并提供的这类特别以明确实验为基础的参数在从事本领域的普通技术人员中是令人满意的。 Select and provide this type of special experiments to clarify the basis of the parameters in the person of ordinary skill in the art is satisfactory.

目前本发明脂质体制剂的非常优选的应用是将其用于治疗下呼吸道包括气管、支气管和肺泡的感染,特别是当所述的脂质体制剂含有聚乙烯吡咯酮碘时。 The preferred application is currently very liposomal formulation of the present invention is for treatment of lower respiratory tract including the trachea, bronchi and pulmonary infection, especially when the liposome preparations contain povidone iodine when. 此外,在这种适应征中,本发明的抗菌制剂、特别是那些含有PVP碘的制剂具有不产生耐受性的主要优点并可导致很低的过敏反应;同时使得具有广谱作用的疗法的费用很低廉。 Further, in such indications, the antimicrobial formulations of the present invention, especially those containing PVP iodine formulations have a major advantage of having no resistance and can result in low allergic reactions; such that while a broad spectrum of action of the therapy the cost is very low. 例如,本发明的聚乙烯吡咯酮碘脂质体制剂可有效地抗病毒。 For example, betadine liposomal formulations of the present invention may be effective against the virus. 此外,杀菌剂诸如聚乙烯吡咯酮碘的脂质体制剂可使所述活性剂从将活性剂转运至肺部区域例如肺泡区域的脂质体中延长释放。 Further, bactericides such as povidone iodine liposome preparation allows the active agent such as liposomes in the alveolar region of the active agent from the extended release transported to the lung area. 与常规的抗菌溶液制剂相比,这将使抗菌物质产生延长作用且由此不需频繁施用。 Compared with conventional antibacterial solution formulation, which will prolong the effect of antibacterial substances and thus do not need frequent administration.

本发明还用于治疗感染性疾病或用于缓解诸如HIV感染这样的伴有机会致病菌感染的疾病。 The present invention is also useful in the treatment of infectious diseases such as HIV infection or to alleviate such opportunistic infections associated with the disease. 还可以按照本发明治疗例如器官移植后带有免疫抑制系统的病人。 It may also be, for example, organ transplantation patients with immunosuppressive therapy system according to the present invention. 特别地,可以用本发明的聚乙烯吡咯酮碘制剂治疗急性或慢性支气管炎、肺炎、支气管扩张、囊性纤维化、白喉、结核。 In particular, with betadine formulation of the invention is the treatment of acute or chronic bronchitis, pneumonia, bronchiectasis, cystic fibrosis, diphtheria, tuberculosis.

此外,非常优选的用途是组织修复,特别是功能和整容组织的改型。 Further highly preferred use is in tissue repair, especially in functional and cosmetic tissue modifications.

本发明的制剂可以采用不同的剂型,这些剂型适合于经下呼吸道给药,包括适合于产生可吸入颗粒的药物上可接受的固体或液体制剂。 Formulations of the invention may take different forms, these forms suitable for the administration via the respiratory tract, including pharmaceutically inhalable particulate pharmaceutical formulation suitable for solid or liquid produced. 因此,本发明的制剂可以是(粉末)气雾剂剂型或致密固体药剂的储备物形式,优选环状片剂、更优选含有所述载体和一种或多种活性剂的胶囊剂、粉剂、喷雾剂、乳剂、分散液、混悬剂乃至溶液。 Accordingly, the formulations of the present invention may be a (powder) reserve or aerosol dosage forms dense solid medicament forms, preferably tablets ring, more preferably the carrier and one or more active agents capsules, powders, sprays, emulsions, dispersions, suspensions and the solution.

一般来说,一方面,本发明制剂中活性剂的量根据所需作用来确定;而另一方面,根据用于所述活性剂的载体制剂的携带容量来确定。 In general, in one aspect, the amount of active agent in the formulation of the present invention is determined according to the desired effect; on the other hand, according to the carrying capacity of the carrier is determined for the formulation of the active agent.

为使本发明的制剂携带大量活性剂或高剂量的活性剂,对于粉剂或粉末气雾剂优选雾化制剂或气雾剂。 To make the formulations of the invention to carry large amounts of active agents or high dosages of active agent, preferably for dusts or powder aerosol nebulizer or aerosol formulation. 概括地说,本发明载体制剂中活性剂的量可以在所述活性剂有效性的低限到所述活性剂在相应载体制剂中的最大承载量之间的浓度范围。 Broadly speaking, the amount of active agent in the formulation of the present invention can be a carrier concentration to a range between a maximum carrying capacity of the active agent in the respective carrier in the formulation of the active agent in the lower limit of effectiveness.

更具体地说,对于抗菌剂诸如聚乙烯吡咯酮碘来说,本发明载体制剂尤其是载体是脂质体的制剂中溶液或分散液可以在100g制剂中含有0.1-10g活性剂。 More specifically, for antibacterial agents such as povidone iodine, the carrier formulation of the present invention in particular carrier is a liposome may contain a solution or dispersion of the active agent in 100g 0.1-10g formulation. 这类制剂一般在每100g制剂中含有1-5g的脂质体成膜物质,特别是卵磷脂。 Such formulations generally contain a liposome forming material 1-5g per 100g of the formulation, in particular lecithins.

本发明气雾剂或喷雾剂通常含有达50mg的脂质体活性剂制剂,而可以含有达到和高于100mg脂质体活性剂制剂且例如可以通过5次喷雾剂量给药,每次含有20mg的脂质体活性剂制剂。 The present invention is generally an aerosol or spray formulations containing liposomes of 50mg of the active agent, and may contain formulation to achieve the active agent and above and 100mg liposomes can be administered by, for example, five times the amount of sprays, each containing 20mg of liposomal active agent formulation.

所述的制剂一般在承载的脂质体(或另一种载体颗粒)中含有至少10%wt的活性剂诸如PVP-碘,而可以含有达50wt.-%乃至50wt.-%以上的活性剂。 The liposome formulation is generally the carrier (or another carrier particles) containing at least 10% wt of active agent such as PVP- iodine, but may contain more than 50wt .-% or even 50wt .-% of the active agent . 如果活性剂是PVP-碘,那么可利用碘的用量一般约为10wt.-%(以PVP-碘为基准)。 If the active agent is PVP- iodine, the iodine may be utilized in an amount generally from about 10wt .-% (with reference to PVP- iodine).

来自实施例的更为具体的制剂是值得关注的。 More specific formulations from Example is noteworthy.

本发明的特征和优点会从随后优选实施方案的描述中更为显著。 Features and advantages of the present invention will become more pronounced from the subsequent description of the preferred embodiments. 在这些包括最佳实施方式的实施方案中,聚乙烯吡咯酮碘是典型的抗菌剂且选择脂质体为载体。 In these embodiments, including the best mode, the betadine antimicrobial agents are typically selected and liposomes as carrier. 然而,尽管这类制剂是特别优选的,但是这不应将本发明限制到抗菌剂或抗菌剂中的聚乙烯吡咯酮碘和/或作为载体的脂质体。 However, although such formulations are particularly preferred, but this should not limit the invention to the liposome antimicrobial or betadine antibacterial agent and / or as a carrier.

制备本发明脂质体的一种优选方法一般如下所述:将脂类成膜成分例如卵磷脂溶于合适的溶剂诸如氯仿或甲醇和氯仿的2∶1的混合物并在无菌条件下过滤。 A preferred method of preparing liposomes of the present invention is generally as follows: The lipid film-forming component such as lecithin dissolved in a suitable solvent such as chloroform or a 2 to 1 mixture of methanol and chloroform and filtered, such as under sterile conditions. 然后,通过控制溶剂的蒸发而使脂类薄膜在高度无菌的表面基质诸如玻璃珠上产生。 Then, a height in the sterile surface of the substrate such as glass beads, by controlled evaporation of the solvent the lipid film. 在某些情况中,可在用于蒸发溶剂的容器内表面上足以形成薄膜而不用特殊基质来增加表面积。 In some cases, it may be sufficient to form a thin film on the inner surface of the container for evaporation of the solvent without a special matrix to increase the surface area.

由电解质成分和(一种或多种)混入所述脂质体制剂中的活性剂来制备含水系统。 The aqueous system is prepared from the electrolyte component and the (one or more) active agents incorporated in the liposome preparation. 这类含水系统例如可以含有10mmol/l磷酸氢钠和0.9%氯化钠、pH为7.4;该含水系统还含有至少所需量的活性剂,在实施例中,该活性剂是聚乙烯吡咯酮碘。 Such aqueous systems may contain, for example 10mmol / l sodium hydrogen phosphate and 0.9% sodium chloride, pH 7.4; the aqueous system further comprises at least a desired amount of the active agent, in an embodiment, the active agent is povidone iodine. 所述的含水系统通常含有过量的一种或多种活性剂。 The aqueous system generally contain an excess of one or more active agents.

通过在有由脂类成分形成的所述薄膜存在的情况下搅拌所述的含水系统一般可以形成脂质体。 Liposomes can generally be formed by an aqueous system in the presence of said film formed by the lipid component of the presence of stirring. 在这一阶段,可以加入另外的添加剂以便改善脂质体制剂;例如,可以加入胆酸钠。 At this stage, further additives can be added to improve liposome formulation; e.g., sodium cholate can be added. 通过机械作用诸如通过例如聚碳酸酯膜加压过滤或离心也可以影响脂质体的形成。 By mechanical action such as pressure filtration through eg polycarbonate membrane or centrifugation may also affect the formation of liposomes. 一般来说,例如用制备上述活性剂的溶液使用的电解质溶液来洗涤粗的脂质体分散液。 Generally, for example, washed with an electrolyte solution was prepared using the above-described active agent to the crude liposome dispersion liquid.

当已经获得具有所需大小分布的脂质体并进行了洗涤时,可以将它们重新分散在如上所述的电解质溶液中,所述的电解质溶液通常还含有糖类诸如蔗糖或合适的糖替代物。 As has been obtained having the desired liposome size distribution and washing, they can be redispersed in an electrolyte solution as described above, the electrolyte solution generally further comprises a saccharide such as sucrose or a suitable sugar substitute . 将所述的分散液冻干并可以将其冷冻干燥。 The dispersion can be freeze-dried and freeze-dried. 在使用前,可以通过加入水并在脂类成分的转变温度下,对于氢化大豆卵磷脂来说例如是55℃,进行适当机械搅拌使冻干物再溶解(reconstitute)。 Prior to use, and by the addition of water at a transition temperature of the lipid component, for example, hydrogenated soybean lecithin for 55 ℃, appropriate mechanical stirring was redissolved lyophilized (reconstitute).

在下列实施例中,使用获自德国Lukas Meyer的氢化大豆卵磷脂(EPIKURON(TM)200SH或获自德国Nattermann Phospholipid GmbH的PHOSPHOLIPON(TM)90H。不过,也可以使用其它药物上可接受的脂质体成膜物质且本领域技术人员会发现易根据现有技术中所述选择合适的另一种脂质体成形系统。 In the following examples, used was obtained from Lukas Meyer, Germany hydrogenated soy lecithin (EPIKURON (TM) 200SH or obtained from Nattermann Phospholipid GmbH of Germany PHOSPHOLIPON (TM) 90H. However, also possible to use other pharmaceutically acceptable liposome filming material and the skilled in the art will easily find a suitable selection of the another liposome forming systems according to the prior art.

实施例Ⅰ在1000ml装有用于增加表面积的玻璃珠的玻璃烧瓶中,将51.9mg胆甾醇和213mg氢化大豆卵磷脂溶于足量的按2∶1比例混合的甲醇与氯仿的混合物中。 Example Ⅰ in 1000ml glass flask equipped with glass beads for increased surface area, the mixture was 51.9mg 213mg of cholesterol and hydrogenated soybean lecithin was dissolved in a sufficient amount according to the mixing ratio of 2 methanol and chloroform. 然后在真空中蒸发溶剂,直到在烧瓶内表面上和玻璃珠上形成薄膜为止。 The solvent was then evaporated in vacuo, until a thin film on the surface of the flask and on the glass beads up.

将2.4gPVP碘(含有约10%的可利用碘)单独溶于12ml水中。 The 2.4gPVP iodine (containing about 10% available iodine) were dissolved in 12ml of water alone.

此外,在单独的容器中,将8.77g氯化钠和1.78g Na2HPO4·2H2O溶于400ml水。 Further, in a separate vessel, 8.77g sodium chloride and 1.78g Na2HPO4 · 2H2O taken up in 400ml water. 再将水加入至980ml的总体积,且然后加入约12ml 1N盐酸以便将pH调节至7.4。 Then water was added to a total volume of 980ml, and then about 12ml 1N hydrochloric acid to adjust the pH to 7.4. 接着用水将该溶液加至精确的1000ml。 The solution was added to water followed by a precise 1000ml.

在第四个容器中,将900mg蔗糖和57mg琥珀酸二钠溶于12ml水。 In a fourth vessel, and 57mg sucrose 900mg disodium succinate were dissolved in 12ml water.

然后将上述PVP碘溶液加入到上述烧瓶中的脂类薄膜上并将混合物振摇至薄膜溶解为止。 The PVP iodine solution was then added to the above said lipid film in the flask and the mixture was shaken until the film dissolved. 从烧瓶中水合脂类中分离出产生的脂质体制剂。 Separating the liposome preparation is produced from the hydrated lipids in the flask. 将产物离心并将上清液弃去。 The product was centrifuged and the supernatant discarded. 将蔗糖溶液加入至12ml并再次将产物离心。 The sucrose solution was added to 12ml and the product was again centrifuged. 此后再次弃去上清液。 After the supernatant was discarded again. 在该阶段,使用蔗糖溶液或氯化钠缓冲溶液进行进一步的洗涤步骤。 At this stage, sucrose or sodium chloride solutions buffered solution further washing step.

在最后的离心步骤并弃去上清液后,加入12ml氯化钠缓冲溶液并使脂质体均匀分布在其中。 After the last centrifugation step and discarding the supernatant, sodium chloride buffer solution was added and 12ml liposomes uniformly distributed therein. 然后将产物分装入各自装有2ml脂质体分散液的管形瓶中并将管形瓶进行冻干步骤。 The product was then dispensed into each liposome dispersion liquid containing 2ml vial and vial lyophilization step.

冻干后,各管形瓶中含有约40mg固体。 After lyophilization, each vial containing about 40mg of solid.

实施例Ⅰ方法具有的较小缺陷在于所用的PVP碘溶液因固体的百分比高而有相当的粘性且由此更难以处理。 Example Ⅰ method has minor defects in that the PVP iodine solution used due to the high percentage of solids and quite viscous and thus more difficult to handle.

实施例Ⅱ在2000ml装有用于增加表面积的玻璃珠的烧瓶中,将173mg氢化大豆卵磷脂和90mg琥珀酸二钠溶于约60ml甲醇/氯仿按2∶1比例混合的混合物中。 Example Ⅱ in 2000ml flask equipped with glass beads for increased surface area, the hydrogenated soybean lecithin 173mg and about 90mg disodium succinate were dissolved in 60ml methanol / chloroform ratio of 2 by mixing the mixture. 在真空中除去溶剂,直到形成薄膜为止。 The solvent was removed in vacuo, until a thin film so far.

将4g PVP碘(10%可利用碘)溶于40ml实施例Ⅰ中所述的氯化钠缓冲溶液并加入到所述烧瓶中的脂类薄膜上。 The 4g PVP iodine (10% available iodine) were dissolved in 40ml sodium chloride buffer solution described in Example Ⅰ and added to the lipid film in the flask. 然后将烧瓶振摇到薄膜溶解和脂质体形成为止。 The flask was then shaken to dissolve the film and liposomes are formed so far.

将产物离心并弃去上清液。 The product was centrifuged and the supernatant was discarded.

向由此产生的脂质体沉淀中再加入40ml氯化钠缓冲溶液并重复离心步骤。 The thus produced liposome pellet 40ml sodium chloride buffer solution was added and the centrifugation step was repeated. 再次弃去上清液。 The supernatant was discarded again. 在该阶段,如果必要,可以重复洗涤步骤。 At this stage, if necessary, a washing step may be repeated.

在最后的离心和倾析步骤后,再次将40ml氯化钠缓冲溶液加入到沉淀的脂质体中。 After the final centrifuging and decanting step, sodium chloride buffer solution was again added to 40ml precipitated liposomes. 然后将均匀的分散液分装入各自装有约2ml脂质体分散液的管形瓶中并将管形瓶进行冻干步骤。 The uniform dispersion is then dispensed into each containing about 2ml tubular liposome dispersion liquid of the vial and vial lyophilization step. 该步骤使得每个管形瓶中产生约200mg的冻干固体。 This step generates so that each vial of lyophilized solid of about 200mg.

类似于实施例Ⅰ,上述方法在薄膜形成后在有有机溶剂存在的情况下使用水合步骤且目的在于包含率为5-15%。 In analogy to example Ⅰ, the above-described method uses a hydration step in the case where the presence of an organic solvent after film formation rate and the object comprises 5-15%. 这些方法一般产生相当大其且通常是多层的脂质体。 These methods generally produce rather large and often it is a multilayer liposome.

在粗脂质体形成后或在随后的任何洗涤步骤后通过经合适膜诸如聚碳酸酯膜的高压过滤步骤或直接通过使用高压匀化法可以改进上述方法。 After the crude liposome formation step or by high pressure filtration through a suitable membrane such as a polycarbonate film or directly by using high pressure homogenization after any subsequent washing step can be improved method described above. 该步骤产生所包裹活性剂的量增加的更小的单层脂质体。 The step of generating the amount of active agent is encapsulated by the smaller increase in unilamellar liposomes.

可以使用公知可产生较小均匀大小脂质体的其它现有技术的方法来替代高压匀化法。 The method may be a known prior art can produce other small uniformly sized liposomes to replace high pressure homogenization process.

实施例Ⅲ由20g含有按照上述一般制备方法得到的冻干(leophilised)物质的聚乙烯吡咯酮碘脂质体和20mg乳糖通过加压至500MPa来制备适合于产生可吸入颗粒的胶囊剂。 Example 20g Ⅲ comprising a lyophilized (leophilised) obtained according to the above general preparation method for a substance betadine liposomes, and 20mg of lactose were prepared by pressure to 500MPa suitable for generating inhalable particles capsules. 通过研磨法,使用粉末吸入器(由Brin Tech International Ltd.产生的Orbital-Inhaler)由获得的硬胶囊来产生粉剂或粉末气雾剂。 By grinding method, the obtained hard capsule a powder or powder to produce a powder inhaler aerosol (generated by Brin Tech International Ltd. Orbital-Inhaler).

还能够制备类似于上述制剂的典型制剂,该制剂含有能够促进伤口愈合的活性剂而不是,和不包括抗菌剂诸如例如在上述实施例中公开的聚乙烯吡咯酮碘。 A typical formulation similar to the above can be also prepared formulation, the formulation comprising an active agent capable of promoting the healing of wounds instead of, and not include betadine antibacterial agents such as, for example, disclosed in the above-described embodiment. 然而,目前优选使用促进伤口愈合的活性剂(如果肯定)以及抗菌剂。 However, it is presently preferred to use a wound healing promoting agent (if positive) and antibacterial agents.

为了给病人施用发明制剂,可以使用公知的系统诸如吸入器、粉末吸入器、双室气压药包、气雾剂喷雾分配器、喷雾器、压缩器等。 For preparation of the invention is administered to a patient, known systems can be used, such as inhalers, powder inhalers, two-chamber gas pressure kits, aerosol spray dispensers, nebulizers, compressors, etc..

实施例Ⅳ通过气动喷雾器来雾化脂质体制剂。 By a pneumatic nebulizer the atomization liposomal Example IV. 已经预先描述了使用气雾剂产生的排出量和脂质体的气雾剂特征。 It has previously described the use of an aerosol wherein the aerosol discharge amount and liposomes produced. 所产生的小滴具有的总的平均气动直径约为2.4μm且由此适合于在肺泡区沉积。 Droplets having a total average aerodynamic diameter of approximately 2.4μm generated and thus adapted to deposit in the alveolar region.

然后使用发明制剂进行功效试验,如下:试验Ⅰ这是由本发明聚乙烯吡咯酮碘脂质体制剂产生的杀菌作用的体外试验。 Then use the formulation for efficacy trials invention is as follows: This is a test in vitro test Ⅰ bactericidal action produced by betadine liposomal formulations of the present invention. 该试验以“Richtlinien der Deutschen Gesellschft fur Hygiene undMikrobiologie”(1989)中所述的定量悬浮试验为基础。 The test in "Richtlinien der Deutschen Gesellschft fur Hygiene undMikrobiologie" the (1989) Quantitative suspension test basis. 在该试验中,将杀菌剂用于杀灭金黄色葡萄球菌(ATCC 29213)、一个医院卫生方面的主要难题。 In this test, the fungicide is used to kill staphylococcus aureus (ATCC 29213), a major problem in hospital hygiene.

所用的脂质体制剂是实施例Ⅰ中所用的脂质体制剂。 Liposome preparation used was a liposomal formulation used in Examples Ⅰ embodiment. 在1-120分钟之间的不同接触时间,测定能够杀灭葡萄球菌属细菌的制剂水溶液的最低浓度。 At different contact times between 120 minutes, the minimum concentration capable of killing assay aqueous formulation of Staphylococcus bacteria.

结果如表1中所示。 The results are shown in Table 1.

表1接触时间(分钟) 杀菌浓度1,2,3,4 ≥0.060%5,30,60 ≥0.015%120 ≥0.007%结果表明在较短的接触时间(1-4分钟)杀菌浓度低到0.06%;而在较长接触时间(120分钟)杀菌浓度可以低到0.007%。 Table 1 contact time (minutes) Bactericidal Concentration 1,2,3,4 ≥0.060% 5,30,60 ≥0.015% 120 ≥0.007% The results showed bactericidal concentration in a short contact time (1-4 minutes) Low 0.06 %; and longer contact times (120 minutes) the bactericidal concentration can be as low 0.007%.

试验ⅡWutzler等已经研究了脂质体PVP-碘在细胞培养物中的杀病毒和杀衣原体活性(参见1999年3月在柏林举行的第9届欧洲临床微生物学和感染疾病会议资料)。 ⅡWutzler and other tests have been studied liposomal PVP- iodine to kill the virus and kill the chlamydia activity in cell cultures (see 9th European clinical microbiology and infectious diseases conference materials held in Berlin in March 1999). 在细胞培养物中,脂质体PVP-碘对单纯疱疹1型病毒和8型腺病毒非常有效,而长期的经大量试验细胞系的细胞毒性实验表明脂质体剂型的可接受性好于含水PVP-碘。 In cell cultures, liposomal PVP- iodine is effective for herpes simplex virus type 1 and adenovirus type 8, while the long-term toxicity test by a large number of cell lines showed acceptability better Liposomal formulations in aqueous PVP- iodine. PVP-碘的脂质体剂型是非基因毒性的。 Liposomal formulations are non-genotoxic PVP- iodine.

试验Ⅲ将3%的PVP-碘水凝胶脂质体制剂与3%的PVP-碘软膏剂进行比较,其中活性剂不是脂质体剂型。 Ⅲ and 3% of PVP- iodine hydrogel liposomal formulations is compared with a 3% PVP- iodine ointment, where the active agent is not a liposomal formulation. 将活性剂施用于大鼠皮肤和腹膜外植体的体外标准化培养物用于筛选皮肤和伤口的抗感染药的组织相容性。 Vitro active agent to the skin and peritoneal explants standardized culture was used to rat tissue compatibility of skin and wound antiinfectives of screening.

在暴露30分钟并用测试物质培养后研究所培养的外植体的生长率。 Exposed for 30 minutes and the growth rate of the test substance is incubated with cultured explants Institute.

此外,根据腹膜生长率和皮肤生长率,在结果中清楚地证明了脂质体制剂的基本上较好的可接受性。 Further, according to the peritoneum growth rate and skin growth rate, the results clearly demonstrated substantially better acceptability liposome formulations.

使用软膏剂的腹膜生长率达到85%,而皮肤的生长率达到90%;使用脂质体水凝胶制剂的腹膜生长率为96%,而皮肤生长率为108%;将这些数值与使用林格溶液作为活性剂的对照试验中的100%数值进行比较。 Use of the peritoneum growth rate reached 85% ointment, and the skin growth rate reached 90%; liposomal hydrogel formulation used in the peritoneum growth rate was 96% and the skin growth rate was 108%; I'm using these values cells was 100% as compared numerical controlled trial of the active agent.

Claims (43)

1. 1. 一种用于制备施用于下呼吸道的抗菌剂和/或促进伤口愈合的活性剂的药物制剂的方法,其特征在于所述的制剂含有至少一种所述活性剂和颗粒载体。 A method for antibacterial and lower respiratory tract of a pharmaceutical formulation and / or wound healing promoting agent is applied to the preparation, wherein the preparation contains at least one active agent and the carrier particles.
2. 2. 权利要求1的方法,其特征在于所述的颗粒载体包括脂质体、微球体、纳米颗粒、大孔颗粒或激光脉冲聚合物包裹的分子中的至少一种。 The method as claimed in claim 1, characterized in that said particulate carrier comprises at least one of liposomes, microspheres, nanoparticles, macroporous polymer particles or a laser pulse wrapped molecule.
3. 3. 根据权利要求1或2所述的方法,其特征在于至少最大部分的所述活性剂包裹在所述载体内部,特别是在脂质体或微球体载体的内部。 The method of claim 1 or claim 2, wherein the active agent is at least the largest part of the package in the inside of the support, especially in the interior of the liposome or microsphere carrier.
4. 4. 根据权利要求1-3中任何一项所述的方法,其特征在于所述的抗菌剂选自释放氧的化合物和释放卤素的化合物;金属化合物诸如银和汞化合物;有机消毒剂特别包括释放甲醛的化合物、醇类、苯酚类包括烷基和芳基苯酚类以及卤代苯酚类、喹啉类和吖啶类、六氢嘧啶类、季铵化合物和亚胺鎓盐、和胍类。 The method according to any of claims 1-3, wherein said compound is selected from an antibacterial agent and oxygen-releasing compounds that release of halogen; metal compounds such as silver and mercury compounds; in particular, organic disinfectants including formaldehyde-releasing compounds, alcohols, phenols including alkyl and aryl phenyl phenols and halogenated phenols, quinolines and acridines, hexahydropyrimidine, quaternary ammonium compounds and iminium salts, and guanidines.
5. 5. 根据权利要求4所述的方法,其特征在于所述的抗菌剂选自下列物质组:金属化合物诸如汞化合物;苯酚衍生物诸如百里酚、丁子香酚和六氯苯;碘和碘配合物。 The method according to claim 4, characterized by the group of substances of the antibacterial agent is selected from: metal compounds such as mercury compounds; phenol derivatives thymol, eugenol and as hexachlorobenzene; Iodine and iodine complex .
6. 6. 根据权利要求5所述的方法,其特征在于所述的抗菌剂是聚乙烯吡咯酮碘。 The method as claimed in claim 5, wherein the antimicrobial agent is povidone iodine.
7. 7. 根据权利要求1-6中任何一项所述的方法,其特征在于所述的促进伤口愈合的活性剂选自促进肉芽发生和上皮形成的活性剂诸如泛醇、尿囊素类、甘菊环烃类、单宁类、来自维生素B系列的化合物或起类似作用的活性剂。 The method according to any of claims 1-6, wherein said wound healing promoting agent selected from agents promoting granulation and epithelialization occurs as panthenol, allantoin type, azulene-based , tannins, compounds from the vitamin B series, or similarly acting agents play.
8. 8. 根据上述权利要求中任何一项所述的方法,其特征在于所述的制剂含有至少一种抗菌剂和至少一种促进伤口愈合的活性剂。 According to any of the preceding claims in a method wherein said formulation comprises at least one antimicrobial agent and at least one active agent to promote wound healing.
9. 9. 根据上述权利要求中任何一项所述的方法,其特征在于所述的载体颗粒,特别是脂质体具有的基本上均匀的大小的范围是约1-约50μm;优选范围约1-约30μm。 The method according to any of the preceding claims, wherein said carrier particles, especially liposomes range having a substantially uniform size is from about 1 to about 50 m; preferably in the range from about 1 to about 30μm .
10. 10. 根据权利要求9所述的方法,其特征在于所述的载体颗粒,特别是脂质体具有的基本上均匀的直径大小的范围是:施用于气管的直径约20μm-30μm;施用于支气管的直径约10μm-20μm;且施用于肺泡的直径约1μm-6μm、特别是在2-5μm。 Applied to the bronchial diameter; administered diameter pipe approximately 20μm-30μm: The method of claim 9, wherein said carrier particles, especially liposomes have a substantially uniform diameter range is about 10μm-20μm; and applied to the alveolar diameter from about 1μm-6μm, particularly in 2-5μm.
11. 11. 根据上述权利要求中任何一项所述的方法,其特征在于所述的载体制剂,特别是脂质体制剂可在延长的时间期限内,优选在几小时持续时间的延长时间期限内释放所述的活性剂。 The method according to any of the preceding claims, wherein said vector preparation, especially a liposomal formulation can be preferably released over a prolonged period of time of several hours duration of the extended period of time in the active agent.
12. 12. 根据权利要求11所述的方法,其特征在于所述的载体制剂,特别是脂质体制剂可在释放时间期限内以大约相同的释放速率释放所述的活性剂。 The method according to claim 11, wherein said vector preparation, especially a liposomal formulation may be at approximately the same release rate of release of the active agent within the release time period.
13. 13. 根据上述权利要求中任何一项所述的方法,其特征在于所述的制剂还含有至少一种麻醉活性剂。 The method according to any of the preceding claims, wherein said formulation further comprises at least one anesthetic agent.
14. 14. 根据上述权利要求中任何一项所述的方法,其特征在于所述的制剂含有添加剂和佐剂诸如保存剂、抗氧化剂和形成稠度的添加剂。 The method according to any of the preceding claims, wherein said formulation contains additives and adjuvants such as preservatives, antioxidants and consistency forming additives.
15. 15. 根据权利要求1-14中任何一项所述的方法,所述的制剂是用于经下呼吸道给药的含有所述活性剂和载体的合适剂型,特别是脂质体剂型、优选气雾剂剂型、尤其是粉末气雾剂剂型。 The method according to any of claims 1-14, said formulation is suitable dosage forms containing the active agent and a carrier for the administration via the respiratory tract, in particular a liposome formulation, preferably an aerosol dosage form, especially powder aerosol dosage forms.
16. 16. 根据权利要求1-14中任何一项所述的方法,所述的制剂是致密固体药剂的储备物形式,优选环状片剂,更优选在药物上可接受的固体或液体制剂中含有所述载体和一种或多种活性剂的胶囊剂、粉剂、喷雾剂、乳剂、分散液、悬乳剂或溶液,它们适合于产生可吸入的颗粒。 The method according to any of claims 1-14, said formulation is storage dense solid form of the agent, preferably a ring tablet, more preferably in a pharmaceutically acceptable solid or liquid formulations containing the capsules carrier and one or more active agents, powders, sprays, emulsions, dispersions, suspoemulsions or solutions, which are suitable for generating inhalable particles.
17. 17. 根据上述权利要求中任何一项所述的方法,所述的制剂是用于经下呼吸道给药的合适剂型,它包括:a)含有药物上可接受的脂质体成膜物质的脂质体;和b)0.1-2%PVP碘溶液(在PVP碘配合物中大约有10%的可利用碘),其中的至少大部分被所述的脂质体膜包裹;其中所述的脂质体的基本上均匀的大小约为1-约50μm且在这种情况下所述的制剂还含有常规的药物制剂的添加剂、佐剂和辅助物质。 The method according to any of the preceding claims, said formulation is a dosage form suitable for administration via the respiratory tract, which comprises: a) liposomes comprising a pharmaceutically acceptable liposome forming substance ; and b) 0.1-2% PVP iodine solution (PVP iodine complex at about 10% of available iodine), wherein at least a majority of the wrap by the liposome; wherein said liposomes substantially uniform size of about 1 to about 50μm and in this case the formulation further comprises additives, adjuvants and auxiliary substances conventional pharmaceutical formulations.
18. 18. 根据权利要求17所述的方法,其特征在于所述的脂质体具有的基本上均匀的直径大小的范围是:施用于气管的直径约20μm-30μm;施用于支气管的直径约10μm-20μm;且施用于肺泡的直径约1μm-6μm、优选约2μm-5μm。 The method according to claim 17, wherein the range of the liposomes have a substantially uniform diameter is: applied to the pipe diameter of approximately 20μm-30μm; administered to the bronchial diameter of about 10μm-20μm; and applied for alveolar diameter from about 1μm-6μm, preferably from about 2μm-5μm.
19. 19. 根据权利要求1-18中任何一项所述的方法,其中所述的制剂适于治疗感染性疾病或缓解诸如HIV感染这样的伴有机会致病菌感染或免疫抑制系统的疾病。 The method according to any of claims 1-18, wherein said formulation suitable for the treatment or alleviation of an infectious disease such as HIV infection accompanied by opportunistic infections or a suppressed immune system diseases.
20. 20. 根据权利要求1-18中任何一项所述的方法,其中所述的制剂适于治疗急性或慢性支气管炎、肺炎、支气管扩张、囊性纤维化、白喉和/或结核。 The method according to any of claims 1-18, wherein said formulation is suitable for the treatment of acute or chronic bronchitis, pneumonia, bronchiectasis, cystic fibrosis, diphtheria and / or tuberculosis.
21. twenty one. 根据权利要求1-20中任何一项所述的方法,其中所述的制剂适于功能和整容组织的改型和修复治疗。 The method according to any of claims 1 to 20, wherein said formulation is adapted modifications and repair functions, and cosmetic tissue treatment.
22. twenty two. 一种预防或治疗人或动物下呼吸道感染的方法,该方法通过给所述的呼吸道施用含有至少一种抗菌剂和/或促进伤口愈合的活性剂的药物制剂来进行,在所述的制剂中所述的活性剂与颗粒载体混合。 A method for the treatment of a human or animal respiratory tract infection or preventing, in at least one antimicrobial agent and / or an active agent to promote wound healing pharmaceutical formulation to the respiratory tract comprising administering to said, in the formulation of the active agent is mixed with the carrier particles.
23. twenty three. 一种在人和动物的下呼吸道中进行功能和整容组织改型和修复的方法,该方法通过给所述的呼吸道施用含有至少一种消炎剂,特别是抗菌剂和/或促进伤口愈合的活性剂以及颗粒载体的药物制剂来进行。 A method for performing the function and cosmetic modifications and tissue repair in the lower respiratory tract in humans and animals, which method comprises administering to the respiratory tract of at least one anti-inflammatory agent, particularly an antibacterial agent and / or promoting wound healing activity agents and a pharmaceutical formulation to particulate carrier.
24. twenty four. 权利要求22或23的方法,其中所述的载体包括脂质体、微球体、纳米颗粒、大孔颗粒或激光脉冲聚合物包裹的分子中的至少一种。 A method as claimed in claim 22 or 23, wherein said at least one carrier comprises liposomes, microspheres, nanoparticles, macroporous polymer particles or a laser pulse wrapped molecule.
25. 25. 权利要求22或23的方法,其中至少最大部分的所述活性剂包裹在所述载体内部,特别是在脂质体或微球体载体的内部。 The method as claimed in claim 22 or 23, wherein the active agent is at least the largest portion of the wrapping inside the carrier, especially in the interior of the liposome or microsphere carrier.
26. 26. 权利要求23的方法,其中所述的消炎剂选自抗菌剂、抗菌素、皮质甾类和促进伤口愈合的活性剂。 The method of claim 23, wherein the antimicrobial agent is selected from anti-inflammatory agents, antibiotics, corticosteroids and agents promoting wound healing.
27. 27. 权利要求22或23的方法,其中所述的抗菌剂选自释放氧的化合物和释放卤素的化合物;金属化合物诸如银和汞化合物;有机消毒剂特别包括释放甲醛的化合物、醇类、苯酚类包括烷基和芳基苯酚类以及卤代苯酚类、喹啉类和吖啶类、六氢嘧啶类、季铵化合物和亚胺鎓盐、和胍类。 A method as claimed in claim 22 or 23, wherein the antimicrobial agent is selected from compounds and halogen-releasing compounds release oxygen; metal compounds such as silver and mercury compounds; in particular, organic disinfectants including formaldehyde-releasing compounds, alcohols, phenols including benzene and alkyl phenols and halogenated aryl phenols, quinolines and acridines, hexahydropyrimidine, quaternary ammonium compounds and iminium salts, and guanidines.
28. 28. 权利要求22或23的方法,其中所述的抗菌剂选自下列物质组:金属化合物诸如汞化合物;苯酚衍生物诸如百里酚、丁子香酚和六氯苯;碘和碘配合物。 A method as claimed in claim 22 or 23, wherein the following group of substances antibacterial agent is selected from: metal compounds such as mercury compounds; phenol derivatives thymol, eugenol and as hexachlorobenzene; iodine and iodine complexes.
29. 29. 权利要求22或23的方法,其中所述的抗菌剂是聚乙烯吡咯酮碘。 A method as claimed in claim 22 or 23, wherein the antimicrobial agent is povidone iodine.
30. 30. 权利要求22或23的方法,其中所述的促进伤口愈合的活性剂选自促进肉芽发生和上皮形成的活性剂诸如泛醇、尿囊素类、甘菊环烃类、单宁类、来自维生素B系列的化合物或起类似作用的活性剂。 The method of 22 or 23 azulene class, tannins claim, wherein said wound healing promoting agent is selected agents promoting granulation and epithelialization occurs such as panthenol, allantoin class, from vitamin B series the compounds or agents that serve similar function.
31. 31. 权利要求22或23的方法,其中所述的制剂含有至少一种抗菌剂和至少一种促进伤口愈合的活性剂。 A method as claimed in claim 22 or 23, wherein said formulation comprises at least one antimicrobial agent and at least one active agent to promote wound healing.
32. 32. 权利要求22或23的方法,其中所述的载体颗粒、特别是脂质体具有的基本上均匀的大小的范围是约1-约50μm;优选范围约1-约30μm。 A method as claimed in claim 22 or 23, wherein the range of the carrier particles, especially liposomes have a substantially uniform size is from about 1 to about 50 m; preferably in the range from about 1 to about 30μm.
33. 33. 权利要求32的方法,其中所述的载体颗粒,特别是脂质体具有的基本上均匀的直径大小的范围是:施用于气管的直径约20μm-30μm;施用于支气管的直径约10μm-20μm;且施用于肺泡的直径约1μm-6μm、特别是在2-5μm。 The method of claim 32, wherein said carrier particles, especially liposomes have a substantially uniform diameter range is: applied to the pipe diameter of approximately 20μm-30μm; administered to the bronchial diameter of about 10μm-20μm; and applied for alveolar diameter from about 1μm-6μm, particularly in 2-5μm.
34. 34. 权利要求22或23的方法,其中所述的载体制剂,特别是脂质体制剂可在延长的时间期限内,优选是在几小时持续时间的延长时间期限内释放所述的活性剂。 A method as claimed in claim 22 or 23, wherein said carrier formulation, in particular the liposomal formulations may be over an extended period of time, preferably in the release of the prolonged period of time of several hours duration of the active agent.
35. 35. 权利要求22或23的方法,其中所述的载体制剂,特别是脂质体制剂可在释放时间期限内以大约相同的释放速率释放所述的活性剂。 A method as claimed in claim 22 or 23, wherein said vector preparation, especially a liposomal formulation may be at approximately the same release rate of release of the active agent within the release time period.
36. 36. 权利要求22或23的方法,其中所述的制剂还含有至少一种麻醉活性剂。 A method as claimed in claim 22 or 23, wherein said formulation further comprises at least one anesthetic agent.
37. 37. 权利要求22或23的方法,其中所述的制剂含有添加剂和佐剂诸如保存剂、抗氧化剂和形成稠度的添加剂。 A method as claimed in claim 22 or 23, wherein said formulation contains additives and adjuvants such as preservatives, antioxidants and consistency forming additives.
38. 38. 权利要求22或23的方法,所述的制剂是用于经下呼吸道给药的含有所述活性剂和载体的合适剂型,特别是脂质体剂型,优选气雾剂剂型,尤其是粉末气雾剂剂型。 The method as claimed in claim 22 or 23, said formulation is suitable dosage forms for the administration via the respiratory tract comprising the active agent and a carrier, in particular a liposome formulation, preferably an aerosol dosage form, especially powder aerosol dosage form.
39. 39. 权利要求22或23的方法,所述的制剂是致密固体药剂的储蓄物形式,优选环状片剂,更优选在药物上可接受的固体或液体制剂中含有所述载体和一种或多种活性剂的胶囊剂、粉剂、喷雾剂、乳剂、分散液、混悬剂或溶液,它们适合于产生可吸入的颗粒。 The method as claimed in claim 22 or 23, the formulations are solid dosage savings in the form of a dense, preferably a ring tablet, more preferably in a pharmaceutically acceptable liquid or solid carrier and said formulation comprising one or more active agents capsules, powders, sprays, emulsions, dispersions, suspensions or solutions, which are suitable for generating inhalable particles.
40. 40. 权利要求22或23的方法,所述的制剂是用于经下呼吸道给药的合适剂型,它包括:a)含有药物上可接受的脂质体成膜物质的脂质体;和b)0.1-2%PVP碘溶液(在PVP碘配合物中大约有10%的可利用碘),其中的至少大部分被所述的脂质体膜包裹;其中所述的脂质体的基本上均匀的大小约为1-约50μm且在这种情况下所述的制剂还含有常规的药物制剂的添加剂、佐剂和辅助物质。 The method as claimed in claim 22 or 23, said formulation is suitable dosage forms for the administration via the respiratory tract, which comprises: a) liposomes comprising a pharmaceutically acceptable liposome membrane material; and b) 0.1 -2% PVP iodine solution (PVP iodine complex at about 10% of available iodine), wherein at least a majority of the said liposomes wrap; wherein said substantially uniform liposome formulation 1- 50μm size of about to about and in this case the further contain additives, adjuvants and auxiliary substances conventional pharmaceutical formulations.
41. 41. 权利要求22或23的方法,其中所述的脂质体具有的基本上均匀的直径大小的范围是:施用于气管的直径约20μm-30μm;施用于支气管的直径约10μm-20μm;且施用于肺泡的直径约1μm-6μm、优选约2μm-5μm。 A method as claimed in claim 22 or 23, wherein said liposomes have a substantially uniform diameter range is: applied to the pipe diameter of approximately 20μm-30μm; administered to the bronchial diameter of about 10μm-20μm; and administered to alveolar diameter from about 1μm-6μm, preferably from about 2μm-5μm.
42. 42. 权利要求22活23的方法,其中所述的制剂适于治疗感染性疾病或缓解诸如HIV感染这样的伴有机会致病菌感染或免疫抑制系统的疾病。 The method of claim 23 living in claim 22, wherein said formulation is adapted to the treatment of infectious diseases or alleviation of a disease such as HIV infection system with such opportunistic infections or immunosuppression.
43. 43. 权利要求22或23的方法,其中所述的制剂适于治疗急性或慢性支气管炎、肺炎、支气管扩张、囊性纤维化、白喉和/或结核。 A method as claimed in claim 22 or 23, wherein said formulation is suitable for the treatment of acute or chronic bronchitis, pneumonia, bronchiectasis, cystic fibrosis, diphtheria and / or tuberculosis.
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